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Memory and learning allow animals to appropriate certain properties of nature with which they can navigate in it successfully. Memory is acquired slowly and consists of two major phases, a fragile early phase (short-term memory, <4 h) and a more robust and long-lasting late one (long-term memory, >4 h). Erythropoietin (EPO) prolongs memory from 24 to 72 h when animals are trained for 5 min in a place recognition task but not when training lasted 3 min (short-term memory). It is not known whether it promotes the formation of remote memory (≥21 days). We address whether the systemic administration of EPO can convert a short-term memory into a long-term remote memory, and the neural plasticity mechanisms involved. We evaluated the effect of training duration (3 or 5 min) on the expression of endogenous EPO and its receptor to shed light on the role of EPO in coordinating mechanisms of neural plasticity using a single-trial spatial learning test. We administered EPO 10 min post-training and evaluated memory after 24 h, 96 h, 15 days, or 21 days. We also determined the effect of EPO administered 10 min after training on the expression of arc and bdnf during retrieval at 24 h and 21 days. Data show that learning induces EPO/EPOr expression increase linked to memory extent, exogenous EPO prolongs memory up to 21 days; and prefrontal cortex bdnf expression at 24 h and in the hippocampus at 21 days, whereas arc expression increases at 21 days in the hippocampus and prefrontal cortex., (© 2024 Wiley Periodicals LLC.)

Synapses can experience long-term enhancements in its efficacy transmission in an activity-dependent manner (LTP, Long-Term Potentiation). This could contribute to store the living experiences in memory. Consequently, loss of synaptic plasticity can lead to failures in memory encoding and storage. Hence, finding ways to restore synaptic function can help restore learning and memory ability. Erythropoietin (EPO) has shown beneficial effects in the brain as a neuroprotector, improving affected learning, memory, and synaptic plasticity among other. In the present study, using the fimbria-fornix lesion model, we address the question whether the administration of erythropoietin restores the synaptic capacity to produce long-lasting increases in their transmission efficiency. A series of experiments was designed in which a control group of healthy young animals and one of injured young animals were formed. A subgroup of injured animals was injected with EPO or the vehicle in which the EPO is diluted (Veh). EPO or Veh was administered 15 min before LTP induction. Our data show that EPO produces a recovery in LTP in the group of fimbria-fornix lesioned animals, which show a severe impairment in the maintenance of LTP. Furthermore, LTP in the injured animals that received EPO was similar to that of the healthy control animals. LTP is widely accepted as a cellular mechanism of memory. Restoring LTP by EPO might be a potential tool for the treatment of memory disturbing diseases like Alzheimeŕs disease. Ongoing clinical trials are evaluating a potential therapeutic effect of low sialic acid-EPO (NeuroEPO) on degenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

An increasing number of reports sustain a possible role of erythropoietin (EPO) as neuroprotective agent. In two previous articles we have evaluated EPO as plasticity promoting agent, and to contribute the restoration of brain function affected by acquired damage. We have shown that EPO is able to induce an increased synaptic efficacy in vivo along with a plasticity promoting effect. In the Morris water maze EPO administration to fimbria-fornix lesioned male rats induces a significant improvement of their spatial memory, affected by the lesion. Singularly, EPO was only effective when administered shortly after training (10 min) but not after several hours (5 h), suggesting a specific EPO effect on time dependent plasticity process. In the present paper we have expanded this line of evidence using a low stress paradigm of object placement recognition in lesioned and healthy male rats. The memory trace in this model is short-lasting; animals could recognize the change in object position when tested 24 h after, but not 48 or 72 h after the acquisition session. EPO administration 10 min after acquisition significantly prolongs retention to, at least, 72 h in healthy rats. No effect was seen if EPO was administered 5 h after training, suggesting a specific EPO modulatory effect on the consolidation process. Remarkably, early EPO treatment to fimbria fornix lesioned animals reverts the memory deficit caused by the lesion. An increased expression of the plasticity related gene arc, was also confirmed in the hippocampus and the prefrontal cortex, that is likely to be involved in the behavioral improvement observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria-fornix chronic-lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up-regulation of plasticity-related early genes. More remarkably, this time-dependent effects on learning recovery could signify that EPO in nerve system modulate specific living-cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long-term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP-Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments., (© 2016 Wiley Periodicals, Inc.)

Background: Erythropoietin (EPO) upregulates the mitogen activated protein kinase (MAPK) cascade, a central signaling pathway in cellular plastic mechanisms, and is critical for normal brain development., Objective: We hypothesized that EPO could modulate the plasticity mechanisms supporting spatial memory recovery in fimbria-fornix-transected animals., Methods: Fimbria-fornix was transected in 3 groups of rats. Seven days later, EPO was injected daily for 4 consecutive days within 10 minutes after training on a water maze task., Results: Our results show that EPO injections 10 minutes after training produced a substantial spatial memory recovery in fimbria-fornix-lesioned animals. In contrast, an EPO injection shortly after fimbria-fornix lesion surgery does not promote spatial-memory recovery. Neither does daily EPO injection 5 hours after the water maze performance. EPO, on the other hand, induced the expression of plasticity-related genes like arc and bdnf, but this effect was independent of training or lesion., Conclusions: This finding supports our working hypothesis that EPO can modulate transient neuroplastic mechanisms triggered by training in lesioned animals. Consequently, we propose that EPO administration can be a useful trophic factor to promote neural restoration when given in combination with training., (© The Author(s) 2015.)